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Novel substituted-1-h-quinazoline-2,4-dione derivatives, preparation method thereof and pharmaceutical composition containing the same

a technology of hquinazoline and derivatives, which is applied in the field of new substituted hquinazoline2, 4dione derivatives, can solve the problems of limited value in most other pharmacological studies, low bioavailability, and low penetration into the cns, and achieve excellent binding affinity and selectivity

Inactive Publication Date: 2009-08-13
KOREA RES INST OF CHEM TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0012]It is therefore an object of the present invention to provide novel substituted-1H-quinazoline-2,4-dione derivatives which can antagonize 5-HT6 with excellent binding affinity and selectivity for 5-HT6 receptors over other receptors, and pharmaceutically acceptable salts thereof.
[0018]As will be apparent later, the novel substituted-1H-quinazoline-2,4-dione derivatives represented by Chemical Formula 1 in accordance with the present invention have excellent binding affinity and selectivity for 5-HT6 receptors over other receptors, inhibit serotonin(5-HT)-stimulated cAMP accumulation, and disrupt apomorphine (2 mg / kg, i.p.)-induced PPI, but cause no rotarod dysfunction when administered in amounts up to 300 mg / kg. Thanks to these effects, the derivatives of the present invention may be useful in the treatment of 5-HT6 receptor-related central nervous system diseases.

Problems solved by technology

The non-selective ligands were useful for investigating the pharmacology of 5-HT6 systems in preparations where other 5-HT receptors were absent (e.g., cAMP assays), however, owing to their lack of selectivity, they were of limited value in most other pharmacological studies.
One problem associated with these antagonists was their low penetration into the CNS.
It was moderately brain penetrant (25%), but subject to rapid blood clearance, resulting in low bioavailability.

Method used

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  • Novel substituted-1-h-quinazoline-2,4-dione derivatives, preparation method thereof and pharmaceutical composition containing the same
  • Novel substituted-1-h-quinazoline-2,4-dione derivatives, preparation method thereof and pharmaceutical composition containing the same
  • Novel substituted-1-h-quinazoline-2,4-dione derivatives, preparation method thereof and pharmaceutical composition containing the same

Examples

Experimental program
Comparison scheme
Effect test

preparation example 2

Preparation of Intermediate I

preparation example 2-1

Preparation of 2-amino-4,6-dichloro-N-methyl-benzamide (Intermediate I-1)

[0170]A solution of 5,7-dichloroanthranilic anhydride (2.00 mmol), methylamine (2.40 mmol) and TEA (2.40 mmol) in tetrahydrofuran or 1,4-dioxane (30 ml) was heated for 2 hours with flux. After the starting material anhydride disappeared, the solvent was removed through vacuum drying. The residue was washed with 1 N hydrochloric acid (100 ml). Recrystallization from a solvent containing methanol, ethylacetate or benzene for corresponding N-substituted benzamide yielded the title compound as a bright brown solid (62%).

[0171]m.p. 159-162° C.;

[0172]1H NMR (200 MHz, CDCl3+CD3OD) δ 2.95 (d, 3H, J=4.9 Hz, NHCH3), 6.63 (d, 1H, J=2.0 Hz, ArH), 6.71 (d, 1H, J=2.0 Hz, ArH), 7.12 (br s, 1H, NH);

[0173]MS (EI) m / e 219 [M+], 188, 148, 133, 73.

preparation example 2-2

Preparation of 2-amino-4,6-dichloro-N-ethyl-benzamide (Intermediate I-2)

[0174]The same procedure as in Preparation Example 2-1, with the exception mat 5,7-dichloroanthranilic acid and ethylamine were used, was performed to give the title compound as a bright brown solid (64%).

[0175]1H NMR (200 MHz, CD3OD) δ 1.25 (t, 3H, J=7.3 Hz, CH3), 3.15 (q, 2H, J=7.3 Hz, NHCH2), 7.01 (d, 1H, J=2.0 Hz, ArH), 8.07 (d, 1H, J=2.0 Hz, ArH);

[0176]MS (EI) m / e 232 [M+], 205, 162, 72.

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Abstract

Disclosed herein are novel substituted-1H-quinazoline-2,4-dione derivatives, a preparation method thereof, and a pharmaceutical composition containing the same. The novel substituted-1H-quinazoline-2,4-dione derivatives are excellent in binding affinity and selectivity for 5-HT6 receptors over other receptors, inhibit serotonin(5-HT)-stimulated cAMP accumulation, and disrupt apomorphine(2 mg / kg, i.p.)-induced hyperactivity in rats. Thanks to these effects, the derivatives are useful in the treatment of 5-HT6 receptor-related central nervous system diseases.

Description

TECHNICAL FIELD[0001]The present invention relates to a novel substituted-1H-quinazoline-2,4-dione derivative, a method for preparing the same, and a pharmaceutical composition containing the same as an active ingredient.BACKGROUND ART[0002]Although its function in the central nervous system has yet to be elucidated, 5-HT has been implicated in the etiology of various disease states, and may be particularly important in mental illnesses, such as depression, anxiety, schizophrenia, eating disorders, obsessive compulsive disorder (OCD), migraines and panic disorder. Recent great advances in pharmacology, molecular biology and genetics on the serotonin system bring the promise of a great improvement in chemical therapy for specific nerve diseases. In practice, many currently used treatments for these disorders are thought to act by modulating serotoninergic tone.[0003]During the last decade, multiple 5-HT receptor subtypes have been characterized. Initially, receptor subtypes were char...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/496C07D403/10A61P25/28
CPCC07D239/96C07D405/06C07D401/06A61P25/00A61P25/06A61P25/18A61P25/20A61P25/22A61P25/24A61P25/28A61P25/30A61P25/32A61P3/04A61P37/02A61P43/00
Inventor SEONG, CHURLMINPARK, NOSANGCHOI, JINILPARK, CHUL MINPARK, WOOKYUKONG, JAEYANG
Owner KOREA RES INST OF CHEM TECH
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